Upload
others
View
5
Download
0
Embed Size (px)
Citation preview
EXONC SERVICE
Optimizing Cardiac Health in Cancer Patients through Exercise
Jessica Scott, PhDExercise Oncology Service
Memorial Sloan Kettering Cancer [email protected]
Twitter: @cardiac_fitness
EXONC SERVICE
No Disclosures
I have no financial relationships to disclose.
I will not discuss off label use and/or investigational use in my presentation.
EXONC SERVICE
Increasing Number of Long Term Cancer Survivors
1920s
Radiation Therapy
1950s
Systemic Therapy
1970s
Screening
2000s
Targeted Therapy
Nu
mb
er o
f Su
rviv
ors
3.6M
16M
26M
2040
ICI
Increased risk of treatment late-effects
& competing causes of mortality
EXONC SERVICE
Cancer Therapy-Induced Cardiovascular Disease
1. Heart Failure Reduced
Ejection Fraction
2. Coronary Artery Disease
3. Heart Failure Preserved
Ejection Fraction
Scott et al. Can J Cardiol., 2016
EXONC SERVICE
Bone Demineralization
Gastrointestinal Events
Immune Dysfunction
Cardiac Atrophy
Skeletal Muscle Atrophy
Exercise Intolerance
Cognitive Impairments
Anemia ‘Direct’ HitCancer / Cancer therapy
‘Indirect’ HitSecondary to cancer /
therapy(e.g., deconditioning)
Baseline risk factorsSmoking, hypertension, age
Cancer Patient
Multiple Hit-Induced Multisystem Deconditioning
EXONC SERVICE
“Accelerated” Cardiovascular Aging
Koelwyn& Jones. J ClinOncol, 2012
10%-20% decrease in VO2peak during treatment
VO2peak remains 30% lower compared to
controls
Long-term cancer survivors 20%-50% increase in CV
events
Multisystem Toxicity Across the Cancer Continuum
EXONC SERVICE
Pulmonary diffusion • no change
Cardiac function • stroke volume• heart rate• cardiac output
Arterial/endothelial function• nitric oxide• angiogenic factors
Skeletal muscle function• mitochondrial size & number• capillarization
Exercise Training to Off-Set the Multiple-Hit
Lakoskiet al.. Nature Rev Clin Oncol, 2012
↑ Cardiorespiratory fitness↓ Fatigue↓ CV risk factors
↓ Chronic morbidity↓ Overt CVD
EXONC SERVICE
Exercise: Standard of Care
Heart disease
Astronauts
Diabetes
Chronic lung disease
Cancer
✓
?
✓
✓
✓
EXONC SERVICE
‘Direct’ HitMicrogravity
‘Indirect’ HitSecondary to microgravity
(e.g., deconditioning)
Baseline risk factorsSmoking, hypertension, age
Bone Demineralization
Gastrointestinal Events
Immune Dysfunction
Cardiac Atrophy
Skeletal Muscle Atrophy
Exercise Intolerance
Cognitive Impairments
Anemia ‘Direct’ HitCancer / Cancer therapy
‘Indirect’ HitSecondary to cancer /
therapy(e.g., deconditioning)
Baseline risk factorsSmoking, hypertension, age
Astronaut Cancer Patient
Multiple Hit-Induced Multisystem Deconditioning
EXONC SERVICE
Spaceflight Countermeasures Program: 1960s1. Phenotyping 2. Exercise During Spaceflight
1965 intervention: 3x10 minutes/day for 14 days
EXONC SERVICE
Spaceflight Countermeasures Program: Current1. Phenotyping
EXONC SERVICE
Spaceflight Countermeasures Program: Current
Prehabilitation
Exercise to
augment reserve
Habilitation
Exercise to
mitigate decline
Rehabilitation
Exercise to return to
baseline levels
1. Phenotyping 2. Exercise Across the Spaceflight Continuum
EXONC SERVICEKoelwyn & Jones J Clin Oncol, 2012
2. Can exercise during therapy mitigate decline / improve
outcomes?
3. Can exercise after therapy or advanced
disease reverse decline / improve outcomes?
4. What is optimal exercise dose / delivery?
% P
hys
iolo
gic
al
Res
erv
e
1. Can exercise prior to therapy augment reserve / improve
outcomes?
Major Gaps in Exercise Oncology
EXONC SERVICEKoelwyn & Jones J Clin Oncol, 2012
% P
hys
iolo
gic
al
Res
erv
e
1. Can exercise prior to therapy augment reserve / improve
outcomes?
Major Gaps in Exercise Oncology
EXONC SERVICEMoore et al. JAMA Intern Med, 2016
Cancer Prevention
Observational Evidence: Cancer and Cardiovascular RiskPre-Diagnosis
Non-Metastatic Breast Cancer (n=4,015)
0
0.2
0.4
0.6
0.8
1
Haz
ard
Rat
io (
CV
D E
ven
ts)
<2.5 2.51-8.6 8.7-18.0 >18.0
37%
Palomo et al. ACC, 2017
CVD Prevention
Favors exercise Favors inactivity
EXONC SERVICE
-10 0 10 20
• n=5 studies
• 205 patients
• 78% male
• GI, NSCLC, Liver, Bladder,
Prostate
• Median 4 week intervention
Scott et al., J Clin Oncol. 2018
Favors exerciseFavors control
Meta-Analysis: VO2peak Pre-therapy
Exercise improves
VO2peak:
MWD: +2.36 mL/kg/min
Pre-therapy
Laukkanenet al., Mayo Clin Proc. 2016
1.0 mL/kg/min increase in VO2peak associated with an
adjusted 9% reduction in
all-cause mortality
EXONC SERVICESebioGarcia. et al., Interact Cardiovasc ThoracSurg, 2016
Exercise reduces post-operative complications:
55% reduced risk
Meta-Analysis: Post-Operative ComplicationsPre-therapy
• n=7 studies
• 548 patients
• 62% male
• Lung cancer
• Median 4 week intervention
Exercise decreases hospital stay: 5 fewer days
EXONC SERVICEKoelwyn & Jones J Clin Oncol, 2012
2. Can exercise during therapy mitigate decline / improve
outcomes?
% P
hys
iolo
gic
al
Res
erv
eMajor Gaps in Exercise Oncology
EXONC SERVICE
-10 0 10 20
• n=14 studies
• 980 patients
• 31% male
• Breast, prostate, lung, hematological
• Median 15 week intervention
Scott et al., J Clin Oncol. 2018
Favors exerciseFavors control
Meta-Analysis: VO2peak During therapy
Exercise improves
VO2peak:
MWD: +1.37
mL/kg/min
Pre-therapy
During therapy
EXONC SERVICE
• n=13 studies
• 1152 patients
• 43% male
• Breast, prostate
• Median 15 week intervention
Meta-Analysis: Muscle During therapy
Exercise improves
muscle strength:
MWD: +26 kg
Exercise improves
lean body mass:
MWD: +0.8 kg
Padilhaet al. J Cancer Surviv,2017
EXONC SERVICEKoelwyn & Jones J Clin Oncol, 2012
3. Can exercise after therapy or advanced
disease reverse decline / improve outcomes?
% P
hys
iolo
gic
al
Res
erv
eMajor Gaps in Exercise Oncology
EXONC SERVICESchmid et al., Ann Oncol, 2014
Breast
RR for All-Cause Mortality, 95% CI
0.0 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.0
Colorectal
Irwin et al., 2008
Holick et al., 2008
Irwin et al., 2011
Beasley et al., 2012
Kuiper et al., 2012
Meyerhardt et al., 2006
Campbell et al., 2013
Meyerhardt et al., 2009
Baade et al., 2011
Meyerhardt et al., 2006Limitations
▪ Small sample sizes (mean, ~3,000 patients)▪ Limited follow-up (<4 years from diagnosis) ▪ Few assessed change in exercise
Observational Evidence: Exercise and Mortality
EXONC SERVICE
• n=15,450 adult survivors of childhood cancer• ~18 years post-diagnosis at baseline• Cumulative incidence at 15 years
0 MET-hrs/weekN=5059
15-18 MET-hrs/weekN=1669
Death from any cause 5.7%11.7% P<0.001
Death from recurrence/progression 1.4% 1.0%P=0.10
Death from health-related causes 8.7% 4.1%P<0.001
Post-Diagnosis Exercise and Cause-Specific Mortality
Scott et al., JAMA Oncol., 2018
Exercise in early adulthood associated with a 42% reduction in all-cause mortality
EXONC SERVICE
Change in Exercise and All-Cause Mortality
Referent
RR for all-cause mortality, 95% CI
0.0 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.0
1.01 (0.81 to 1.27)
Low maintenance (n=1677)
Decreased exposure (n=2279)
0.60 (0.44 to 0.82)Increased exposure (n=1174)
0.56 (0.36 to 0.88)High maintenance (n=559)
•n=5,689• 8 yrs
Scott et al., JAMA Oncol., 2018
0
-6
+6
0
MET-hrs/week change
Baseline Follow up 2
Increased or high exercise over 8 years associated with ~40% reduction in
all-cause mortality
EXONC SERVICE
-10 0 10 20
• n=27 studies
• 1774 patients
• 26% male
• Breast, colorectal, prostate, lung,
testicular, brain
• Median 13 week intervention
Scott et al., J Clin Oncol. 2018
Favors exerciseFavors control
Pre-therapy
During therapy
Post-therapy
Exercise improves
VO2peak:
MWD: +2.45
mL/kg/min
Meta-Analysis: VO2peak Post-therapy
EXONC SERVICE
Exercise RCT in Metastatic Breast CancerAdvanced disease
Safety:- Serious AE: 0%- Non-serious AE (fatigue, pain): 10%
Feasibility:- Dose modification: 49%- Dose interruption: 46%- Relative dose intensity: 61%
Aerobic training at the dose and schedule tested is safe but not feasible for a significant proportion of
patients with metastatic breast cancer
Scott et al., Cancer, 2018
EXONC SERVICEKoelwyn& Jones. J ClinOncol, 2012
5%-10% increase in VO2peak pre/during
treatment
10-20% increase in VO2peak post treatment
20%-40% decreased risk of CV events
Summary I: Exercise Training Across the Cancer Continuum
EXONC SERVICE
EXONC SERVICE
Existing
CVDNone
Impairment in Physical
Functioning - Speech
Cardiac
SymptomsHx MI or PCI/CABG,
↓LVEF, valvular dxNone
Low-dose
anthracycline
+ trastuzumab
Low-dose anthracycline
or trastuzumab + ≥2 RF,
or age ≥ 60 yrs
High-dose
anthracycline/
radiotherapy*
None
or
other
Cardiopulmonary
exercise test
Oncology/Cancer
rehabilitationCardio-oncology
rehabilitation exercise
(CORE)
Community-based
programs for cancer
patients
CV
consult
PT /OT / speech
consult
No symptoms/dxAfter exposure, assess symptom/dx
No symptoms/dx
EXONC SERVICE
NCCN: Delingeret al. NCCN2014
ACS: Rock et al. CA Cancer J Clin, 2012
ACSM: Schmitz et al. Med SciSports Exer, 2010
ACS...Avoid inactivity
....≥150 mins/wk of mod-
intensity or ≥75 mins/wk
vig-intensity aerobic
activity
....greater benefits: ≥300
mins/wk of mod-intensity
or ≥150 mins/wk vig-
intensity aerobic activity
“ ”“
”“
”
ONE SIZE, FITS ALL!
Research Gaps
EXONC SERVICE
Current Practice“One size fits all”
Positive responders
Non responders
Personalized MedicinePrecision exercise prescription
Risk stratification
Risk Stratification and Precision Exercise
One size fits all
Positive responders
Scott et al., Circulation, 2018
EXONC SERVICEKoelwyn & Jones J Clin Oncol, 2012
4. What is optimal exercise dose / delivery?
% P
hys
iolo
gic
al
Res
erv
eMajor Gaps in Exercise Oncology
EXONC SERVICE
External Load Internal Load
Non-Cancer
Internal Exercise LoadCycling at 350W
(75% VO2peak) for 60 min
Patient
External Load Internal Load
Exercise Training Load –Adaptation ResponseExercise dosing
EXONC SERVICE
Desired Physiological Adaptation or Study
Outcome
Effects of theDisease/Therapy
Patient Limitations
Comorbidities / Confounders
Exercise Training Prescription
Exercise Program Design Considerations Exercise dosing
EXONC SERVICE
Principles of Exercise TrainingExercise dosing
EXONC SERVICE
Cardiac Function
Blood Volume
&RBCs
Vasodilatory
Signaling
Neuromuscular Function
Metabolic
Adaptation
Mitochondrial Biogenesis
Autonomic Regulation
VT1/ LT1 VT2/ LT2 VO2peak
Zone 1 – Recovery Zone 2 – LSD Zone 3 – Tempo Zone 5 – IntervalsZone 4 – Threshold
CapillaryDensity
Exercise SpecificityExercise dosing
EXONC SERVICE
% In
ten
sity
50
100
0
0 63
Months
Non-linear
% In
ten
sity
50
100
0
0 63
Months
Linear, moderate intensity
100
00 63
Months
50
Linear, high intensity
? Safe ✓ Moderate efficacy
Current guidelines Alternative 1 Alternative 2
X Questionable safety ✓High efficacy
✓ Adheres to principles of exercise training
% In
ten
sity
Exercise SequencingExercise dosing
EXONC SERVICE
1. Multisystem Physiologic Characterization
2. Individualized Exercise Prescription
3. Supervised Physiologic Monitoring and Data Capture
Vascular
Blood
Cardiac
VO2peak
MSK Exercise Oncology Approach
EXONC SERVICE
Risk Stratification Prescription
Standard exercise guidelinese.g., 3d/wk, 30-60 min/session at 70%-80% of peak heart rate
VO2peak-based prescriptione.g., 3d/wk, 30-60 min/session with each session at individualized VO2-based intensity zones
High CV risk + CPETe.g., clonal hematopoiesis
ASCO cardiotoxicity guidelinese.g., patients receiving high-dose anthracycline
Scott et al. Circulation, 2018
Future Directions
EXONC SERVICE
Bone Marrow
Normal HSC
HSC + 1 Mutation
HSC + 2 Mutations
Extrinsic: Radiation, Chemotherapy
Intrinsic: Aging
...
....
..
......
...
High CV Risk: Clonal Hematopoiesis (CH)
..
..
..
..
..
..
Peripheral Blood
Myeloid cells
Lymphoid cells
. .. ... ..
....
.. . .
Proinflammatory
mediators
Organs
HFrEF
CAD
EXONC SERVICE
Baseline Follow-Up
EXERCISE
Study Cohort
- Confirmed CH
- Completion of therapy
for solid tumors
- Inactive (<150 min/wk)
DYNAMIC LIFESTYLE MONITORINGASSESSMENTS ASSESSMENTS
6
MONTHS
Exercise as Interception Therapy for CHFuture directions
EXONC SERVICE
4
2
A K T I V A G A I N S T
C A N C E R E X E R C I S E
O N C O L O G Y C E N T E R
M A N H A T T A N
42
Exercise Training Delivery
3 days/week, for 20-60 mins
Future directions
EXONC SERVICE
EXONC SERVICE
Delivery Set-up and Device Integration Real-Time Monitoring
Tele-ExerciseFuture directions
EXONC SERVICE
R O C K V I L L E C E N T R E
M O N M O U T H
B R O O K L Y N
C O M M A C K
H A U P P A U G EB E R G E N
W E S T C H E S T E R
B A S K I N R I D G E
A K T I V A G A I N S T
C A N C E R E X E R C I S E
O N C O L O G Y C E N T E R
M I S S I O N C O N T R O L
Exercise Training DeliveryFuture directions
EXONC SERVICE
Conclusions
• Cancer treatment :
– accelerates cardiovascular aging
– increases risk of competing causes of morbidity & mortality
• Exercise therapy:–mitigates accelerated cardiovascular aging
– one size does not fit all
EXONC SERVICE
MSK• Lee Jones
• Chau Dang
• Anthony Yu
• Pedram Razavi
Exercise-Oncology Team
Acknowledgments
EXONC SERVICE
Optimizing Cardiac Health in Cancer Patients through Exercise
Jessica Scott, PhDExercise Oncology Service
Memorial Sloan Kettering Cancer [email protected]
Twitter: @cardiac_fitness